STAT6 polymorphisms are associated with neonatal regulatory T cells and cytokines and atopic diseases at 3 years
STAT6 polymorphisms are associated with neonatal regulatory T cells and cytokines and atopic diseases at 3 years
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DOI：
10.1111/all.12220
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发表时间：
2013-10-01
期刊：
影响因子：
12.4
通讯作者：
Schaub, B.
中科院分区：
文献类型：
--
作者：
Casaca, V. I.;Illi, S.;Schaub, B.
背景转录因子STAT 6对于白细胞介素（IL）-4/IL-13途径的激活至关重要，并且与调节性T细胞（Treg）有关。STAT 6基因多态性与IgE水平的关联已被描述，但其对新生儿免疫应答和早期疾病发展的影响尚不清楚。方法采用基质辅助激光解吸电离飞行时间质谱（MALDI-TOF-MS）技术对脐血单个核细胞中STAT 6基因多态性进行分型。通过实时聚合酶链反应（PCR）和Multiplex评估基因表达和细胞因子。结果STAT 6基因rs324011多态性与Treg相关基因（FOXP 3、GITR、LAG 3）mRNA表达显著或边缘显著降低相关，而与rs 1059513多态性无关。rs324011杂合子和次要等位基因纯合子的TNF-α水平较低，IFN-γ水平较高（P0.04），而rs 1059513杂合子和次要等位基因纯合子的TNF-α和GM-CSF水平较高（P0.05）。在rs324011的次要等位基因纯合子中，Treg相关基因的表达与IFN-γ呈强负相关（未刺激，r=-0.7，P=0.111; LpA刺激，r=-0.8，P=0.011），但在杂合子或主要等位基因纯合子中不相关。rs324011基因杂合子和次等位基因纯合子在3岁以前发生特应性皮炎和阻塞性支气管炎的风险较低。STAT 6 rs324011与较低的新生儿Treg和增加的Th 1应答相关。这些新生儿在30岁前患异位性皮炎和阻塞性支气管炎的风险较低。我们的数据表明STAT 6多态性在早期免疫调节中的作用以及对早期特应性疾病发展的影响。
BackgroundThe transcription factor STAT6 is crucial for activation of the interleukin (IL)-4/IL-13 pathway and has been linked to regulatory T cells (Tregs). Associations of STAT6 polymorphisms with IgE levels were described; however, their impact on neonatal immune responses and early disease development is unknown.MethodsSTAT6 polymorphisms were genotyped in cord blood mononuclear cells by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). Gene expression was assessed by real-time polymerase chain reaction (PCR) and cytokines by Multiplex. At age 3years, atopic diseases were assessed by questionnaires.ResultsSTAT6 rs324011 but not rs1059513 polymorphism was associated with significant or borderline significant decreased mRNA expression of Treg-associated genes (FOXP3, GITR, LAG3). Heterozygotes and minor allele homozygotes of rs324011 had low levels of tumor necrosis factor alpha (TNF-) and increased interferon gamma (IFN-) (P0.04), while heterozygotes and minor allele homozygotes of rs1059513 had increased TNF- and Granulocyte-macrophage colony-stimulating factor (GM-CSF) (P0.05). In minor allele homozygotes of rs324011, expression of Treg-associated genes was strongly inverse correlated with IFN- (unstimulated, r=-0.7, P=0.111; LpA stimulation, r=-0.8, P=0.011), but not in heterozygotes or major allele homozygotes. Heterozygotes and minor allele homozygotes of rs324011 presented a lower risk of atopic dermatitis and obstructive bronchitis until age 3years.ConclusionsTwo STAT6 polymorphisms were associated with altered immune responses already at birth. STAT6 rs324011 was associated with lower neonatal Treg and increased Th1 response. Those neonates had a lower risk of atopic dermatitis and obstructive bronchitis until 3years. Our data suggest a role for STAT6 polymorphisms in early immune regulation and implications on early atopic disease development.